Pharmacokinetics

Absorption

Well absorbed from the GI tract. The tablets slowly release the drug over several hours. Conjugated estrogens are water-soluble and well absorbed through the skin, mucous membranes, and GI tract.

Vagifem

C max is 50 pg/mL over a 12-wk course without accumulation.

Vaginal ring

T max is 0.5 to 1 h; it then declines at a relatively constant rate for the following 90 days.

Distribution

Bound to sex hormone–binding globulin and albumin. Widely distributed and generally found in higher concentrations in the sex hormone target organs. Crosses the placenta.

Metabolism

Partially metabolized by CYP3A4. Metabolized in the liver and undergoes enterohepatic recirculation. Estradiol is converted reversibly to estrone, and both can be converted to estriol (major urinary metabolite).

Elimination

Estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

Vaginal ring

The mean percent excreted in the 24-h urine as estradiol 4 and 12 wk after application is 5% and 8%, respectively, of the daily released amount.

Indications and Usage

Conjugated or esterified estrogens

Treatment of moderate to severe vasomotor symptoms associated with menopause; treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause; treatment of hypoestrogenism caused by hypogonadism, female castration, or primary ovarian failure; palliative treatment of metastatic breast cancer in selected women and men; palliative treatment of advanced androgen-dependent carcinoma of the prostate.

Conjugated estrogens

Prevention of postmenopausal osteoporosis.

Conjugated estrogens, parenteral form

Short-term treatment of abnormal uterine bleeding caused by hormonal imbalance in the absence of organic pathology.

Treatment of moderate to severe vasomotor symptoms associated with menopause; treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause.

Premarin vaginal cream

Treatment of atrophic vaginitis and kraurosis vulvae; treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy associated with menopause.

Vagifem

Treatment of atrophic vaginitis.

Contraindications

Breast cancer (except in patients being treated for metastatic disease); estrogen-dependent neoplasia; undiagnosed abnormal genital bleeding; known or suspected pregnancy; active deep vein thrombosis (DVT), pulmonary embolism (PE), or a history of these conditions; active or recent (within past year) arterial thromboembolic disease (eg, MI, stroke) or a history of these conditions; liver dysfunction or disease; known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; hypersensitivity to any component of the product.

Intravaginal 0.5 g in a cycle of 21 days of therapy daily followed by 7 days of no therapy. Dosage adjustments (0.5 to 2 g) may be made based on individual response.

Dyspareunia due to menopauseAdultsPremarin vaginal cream

Intravaginal 0.5 g twice weekly (eg, Monday and Thursday) as a continuous regimen or in a cycle of 21 days of therapy daily followed by 7 days of no therapy.

Breast CancerAdultsConjugated estrogens

PO 10 mg 3 times daily for 3 mo or more.

Female Castration, Primary Ovarian FailureAdultsConjugated estrogens

PO 0.3 to 1.25 mg/day cyclically (3 wk on estrogen, 1 wk off).

Esterified estrogens

PO 1.25 mg/day cyclically (3 wk on estrogen, 1 wk off).

Female HypogonadismAdultsConjugated estrogens

PO 0.3 to 0.625 mg/day cyclically (3 wk on estrogen, 1 wk off).

Esterified estrogens

PO 2.5 to 7.5 mg/day in divided doses for 20 days, followed by a 10-day rest period. If bleeding does not occur at the end of this schedule, the schedule is repeated.

Kraurosis VulvaeAdultsPremarin vaginal cream

Intravaginal 0.5 g in a cycle of 21 days of therapy daily followed by 7 days of no therapy. Dosage adjustments (0.5 to 2 g) may be made based on individual response.

Postmenopausal OsteoporosisAdultsConjugated estrogens

PO Start with 0.3 mg daily and adjust dose based on individual clinical and bone mineral density responses. May be given continuously or in a cyclical regimen (eg, 25 days on drug followed by 5 days off drug).

Vaginal ring Insert 1 ring as deeply as possible into upper one-third of vaginal vault. Ring is to remain in place for 90 days, after which it is to be removed and replaced by a new ring if necessary. The need to continue treatment should be assessed at 3- or 6-mo intervals.

Vasomotor SymptomsAdultsConjugated estrogen

PO Start with 0.3 mg daily and adjust dose based on individual patient response. May be given continuously or in a cyclical regimen (eg, 25 days on drug followed by 5 days off drug).

Esterified estrogens

PO 1.25 mg/day.

Femring

Vaginal ring Start with vaginal ring delivering estradiol 0.05 mg/day inserted into the vagina. It should remain in place for 90 days, then be removed and replaced with a new vaginal ring if needed.

Vulvar and Vaginal Atrophy SymptomsAdultsConjugated estrogens

PO Start with 0.3 mg daily and adjust dose based on individual patient response. May be given continuously or in a cyclical regimen (eg, 25 days on drug followed by 5 days off drug).

Intravaginal Usual dose range is 2 to 4 g daily for 1 to 2 wk; then gradually reduce to 50% of the initial dose for a similar period. A maintenance dosage of 1 g 1 to 3 times weekly may be used after restoration of the vaginal mucosa has been achieved.

Femring vaginal ring

Intravaginal Start with vaginal ring delivering estradiol 0.05 mg/day inserted into the vagina. It should remain in place for 90 days, then be removed and replaced with a new vaginal ring if needed.

General Advice

Administer parenteral form immediately after reconstitution.

Do not shake parenteral form vigorously.

To clean vaginal applicator, remove plunger from barrel and wash it with mild soap and warm water. Do not boil or use hot water.

Conjugated estrogens

Administer IM injection deeply into muscle.

Administer IV injection slowly to avoid flushing.

Infusion of conjugated estrogen with other agents is not recommended. Solution is compatible with normal saline, dextrose, and invert sugar solutions. It is not compatible with any solution with acidic pH.

Using the supplied applicator, gently insert vaginal tablet into the vagina as far as it can comfortably be inserted without force.

Estrace vaginal cream has a calibrated plastic applicator for delivery. Do not separate the plunger from the applicator.

Conjugated estrogen IV is not compatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH.

Vaginal ring

To insert, press the ring into an oval and place in the upper one-third of the vaginal vault. The exact position is not critical.

If there is discomfort, the ring is probably not far enough inside. The ring should gently be pushed farther into the vagina.

Some women have experienced moving or gliding of the vaginal ring within the vagina. Instances of expulsion have been reported. If this occurs, Estring can be rinsed in lukewarm water and reinserted.

The ring may be removed by hooking a finger through the ring and pulling it out.

Esterified estrogens

Administer as prescribed without regard to meals.

Administer with food if GI upset occurs.

Storage/Stability

Estrace vaginal cream

Store at room temperature. Protect from temperatures exceeding 104°F.

Estring , Femring

Store at 59° to 86°F.

Injection

Store vials for parenteral administration in the refrigerator at 36° to 46°F.

Tablets, Premarin vaginal cream, vaginal tablets

Store at 59° to 86°F.

Drug Interactions

Corticosteroids (eg, prednisone)

Increased pharmacologic and toxicologic effects of corticosteroids may occur.

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Undertake diagnostic measures, including endometrial sampling when indicated, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Monitor

Monitor BP at beginning of therapy and at regular intervals during treatment. Periodically monitor thyroid function. Monitor blood glucose levels in diabetic patients; monitor more frequently when therapy is started and the dose is changed.

Baseline examinations

Ensure that breast, abdominal, and pelvic examination and Pap smear have been completed and documented before starting therapy and annually thereafter during prolonged therapy.

Pregnancy

Contraindicated in pregnancy.

Vagifem

Category X .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Estring

There have not been sufficient numbers of elderly patients involved in studies to determine whether those older than 65 y differ in response from younger subjects. Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hypersensitivity

Cases of anaphylaxis, which develop within minutes to hours after taking orally administered conjugated estrogens, may occur. Angioedema requiring medical intervention has occurred. Estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Hepatic Function

Metabolism may be impaired; use drug with caution. Contraindicated in patients with liver dysfunction or disease.

Special Risk Patients

Because asthma, diabetes mellitus, epilepsy, hepatic hemangiomas, migraine, porphyria, severe hypocalcemia, and SLE may be exacerbated by estrogens, use with caution.

Barrier contraceptives

Premarin vaginal cream may weaken latex condoms, which may contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber.

Calcium/Phosphorus metabolism

Use drug with caution in patients with metabolic bone diseases.

Elevated BP

BP elevation may occur.

Endometrial hyperplasia

A higher incidence of endometrial hyperplasia was reported in women receiving continuous estrogen alone compared with those receiving coadministration of a progestin. Endometrial hyperplasia may be a precursor to endometrial cancer.

Gallbladder disease

Glucose intolerance

Hepatic adenoma

Consider the possibility in patients with abdominal mass, abdominal pain and tenderness, or hypovolemic shock.

Hypercalcemia

Severe hypercalcemia in patients with breast cancer and bone metastases may occur.

Hypertriglyceridemia

In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations in plasma triglycerides, leading to pancreatitis.

Hypoparathyroidism

Use with caution; estrogen-induced hypocalcemia may occur.

Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin levels. Ensure that thyroid function is periodically monitored in patients with hypothyroidism and that thyroid-replacement dose is adjusted, if necessary, to maintain free thyroid levels in an acceptable range.

Induction of malignant neoplasms

May increase the risk of endometrial or other carcinomas.

Ovarian cancer

Estrogen plus progestin and estrogen-only products, in particular for more than 5 y, have been associated with an increased risk of ovarian cancer.

Surgery/Immobilization

Consider discontinuing therapy during periods of prolonged immobilization and, if possible, 4 wk before surgery that is associated with an increased risk of thromboembolic disease.

Tapering/Withdrawal

Attempts should be made every 3 to 6 mo to discontinue therapy or reduce the dose of medication.

Toxic shock syndrome

Has been reported.

Unopposed estrogen administration (eg, without progesterone)

Increases risk of uterine cancer; therefore, when using estrogens on a long-term basis in a woman with an intact uterus, consider cyclic therapy with progesterone (eg, estrogen on days 1 to 25 of mo with progesterone added for last 12 days) or coadministration of estrogen plus progesterone on daily basis. In a woman without a uterus, use of cyclic therapy or therapy with progesterone is not necessary.

Vaginal irritation

Estradiol vaginal ring may not be suitable for women with narrow, short, or stenosed vaginas, or conditions that make the vagina more susceptible to irritation or ulceration.

Visual abnormalities

Retinal vascular thrombosis may occur, leading to diplopia, loss of vision, migraine, or sudden onset of proptosis.

Remind patients to have a Pap smear every 6 to 12 mo while undergoing therapy.

Inform patients that it may take 2 to 3 wk to feel the full effects of the estradiol vaginal ring in relieving vaginal and urinary symptoms and to contact their health care provider if symptoms persist more than a few weeks.

Instruct patients to contact their health care provider if, after insertion of the vaginal ring, vaginal secretions are associated with a bad odor or vaginal discomfort or itching.

Instruct patients that after 90 days there will not be enough estradiol in the vaginal ring to maintain its full effect and, if their health care provider determines that there is a need to continue therapy, that they should remove the ring at that time and replace it with a new ring.

Instruct patients to remove the estradiol vaginal ring and immediately contact their health care provider if they are experiencing diarrhea, dizziness, faintness, fever, muscle pain, nausea, a sunburn-rash on face or body, or vomiting.

Inform patients that Premarin vaginal cream may weaken latex condoms and other forms of barrier contraceptives.